An inhibitor of the interaction between the transcription factor NRF2 and the E3 ligase adapter β-TrCP suppresses lipopolysaccharide- mediated inflammation.

Abstract

Inflammation plays a crucial role in the pathology of most chronic diseases, such as neurodegenerative and metabolic disorders. Transcription factor NRF2 has been proposed recently as a promising target to generate a beneficial therapeutic effect in most chronic diseases characterized by low-grade oxidative stress and inflammation. Most of the compounds identified as NRF2 activators are electrophiles that inhibit its main repressor: KEAP1. However, electrophiles display many off-target effects and elicit a supra-physiological NRF2 activation. As an alternative, we identified a small molecule that disrupts the interaction between NRF2 and its other repressor E3 ubiquitin ligase β- TrCP. In vitro and cell culture experiments demonstrated that our hit small molecule is a β-TrCP/NRF2 interaction inhibitor. This compound is specific for NRF2 and not for the other substrates described for β-TrCP, such as β-Catenin. Moreover, it attenuates the production of pro-inflammatory markers in cultured macrophages submitted to the endotoxin lipopolysaccharide (LPS). In vivo pharmacodynamics studies demonstrated selective exposure and NRF2 activation in liver. In mice submitted to LPS-induced acute liver inflammation, the compound greatly attenuated Kupffer cells activation and the NFkB-mediated inflammatory response. These findings report an innovative mechanism to activate NRF2 and it could be used as an alternative to conventional anti-inflammatory therapies.